Human β-Amyloid 40 (hAβ40) Kinetics after Intravenous (IV) and Intracerebroventricular (ICV) Injections and Calcitriol Treatment in Rats in vivo

Amyloid-β peptides of 40 and 42 amino acid lengths, which are synthesized in neurons and degraded in the brain and liver, have the potential to aggregate and form neuritic plaques in Alzheimer's disease (AD). The kinetics of human Aβ40 (hAβ40) was examined in the rat pursuant to intravenous (IV) and intracerebroventricular (ICV) administration after pretreatment with calcitriol, the active vitamin D receptor ligand [6.4 nmol·kg-1 in 0.3 mL corn oil every other day for 4 intraperitoneal (IP) doses] to induce P-glycoprotein (P-gp) and enhance hAβ40 brain efflux. The interference of hAβ40 by media matrix that suppressed absorbance readings in the ELISA assay was circumvented with use of different calibration curves prepared in Standard Dilution Buffer, undiluted, 10-10,000 or 5-fold diluted plasma, or artificial cerebrospinal fluid. Simultaneous fitting of hAβ40 plasma and CSF data after IV and ICV administration were described by catenary-mammillary models comprising of a central and two peripheral compartments, the brain, and one CSF to four compartments. The model with only one CSF compartment (Model I) best fitted the IV data that showed a faster plasma decay t1/2 and slower equilibration between plasma and brain/CSF. Calcitriol induction increased brain efflux rate constants, k41 (1.8-fold) at the blood-brain barrier (BBB), when compared to the control group, as confirmed by the 2-fold (P < 0.05) increase in brain P-gp relative protein expression. SIGNIFICANCE STATEMENT: An accurate description of hAβ40 that reflects the kinetic behavior of the toxic peptide is needed in defining it as a biomarker of Alzheimers disease. Modeling of hAβ40 data after intravenous and intracerebroventricular administration to the rat revealed an initially faster plasma half-life that reflects faster peripheral distribution but slower equilibration between plasma and brain/CSF; with calcitriol pretreatment, which increased P-gp protein expression in brain, clearance was enhanced due to increased P-gp protein expression for hAβ40 efflux from brain.

Keywords: blood-brain barrier; brain/CNS; efflux transporters (P-gp, BCRP, MRP, MATE, BSEP, etc); pharmacokinetics; protein binding.